tbuckley/cabot-search huggingface dataset:
Clinical characteristics and overall survival among acute myeloid leukemia patients with <scp><i>TP53</i></scp> gene mutation or chromosome 17p deletion
Authors: Naval G. Daver, Shahed Iqbal, Julie Huang, Camille Renard, Joyce Lin, Yang Pan, Mellissa Williamson, Giridharan Ramsingh
Journal: American Journal of Hematology (2023)

Abstract Approximately 5% to 15% of acute myeloid leukemia (AML) patients have TP53 gene mutations ( TP53 m), which are associated with very poor outcomes. Adults (≥18 years) with a new AML diagnosis were included from a nationwide, de‐identified, real‐world database. Patients receiving first‐line therapy were divided into three cohorts: venetoclax (VEN) + hypomethylating agents (HMAs; Cohort A), intensive chemotherapy (Cohort B), or HMA without VEN (Cohort C). A total of 370 newly diagnosed AML patients with TP53 m (n = 124), chromosome 17p deletion (n = 166), or both (n = 80) were included. The median age was 72 years (range, 24–84); most were male (59%) and White (69%). Baseline bone marrow (BM) blasts were ≤30%, 31%–50%, and &gt;50% in 41%, 24%, and 29% of patients in Cohorts A, B, and C, respectively. BM remission (&lt;5% blasts) with first‐line therapy was reported in 54% of patients (115/215) overall, and 67% (38/57), 62% (68/110), and 19% (9/48) for respective cohorts (median BM remission duration: 6.3, 6.9, and 5.4 months). Median overall survival (95% CI) was 7.4 months (6.0–8.8) for Cohort A, 9.4 months (7.2–10.4) for Cohort B, and 5.9 months (4.3–7.5) for Cohort C. There were no differences in survival by treatment type after adjusting for the effects of relevant covariates (Cohort A vs. C adjusted hazard ratio [aHR] = 0.9; 95% CI, 0.7–1.3; Cohort A vs. B aHR = 1.0; 95% CI, 0.7–1.5; and Cohort C vs. B aHR = 1.1; 95% CI, 0.8–1.6). Patients with TP53 m AML have dismal outcomes with current therapies, demonstrating the high unmet need for improved treatments.
Bile exosomal miR-182/183-5p increases cholangiocarcinoma stemness and progression by targeting HPGD and increasing PGE2 generation
Authors: Lizhuang Shu, Xingyong Li, Zengli Liu, Kangshuai Li, Anda Shi, Yongchang Tang, Liming Zhao, Lingling Huang, Zhiyue Zhang, Dong Zhang, Shaohui Huang, Shuo Lian, Guoli Sheng, Zhangdi Yan, Zongli Zhang, Yunfei Xu
Journal: Hepatology (2023)

Background &amp; Aims: Cholangiocarcinoma (CCA) is a highly lethal malignancy originating from the biliary ducts. Current CCA diagnostic and prognostic assessments cannot satisfy the clinical requirement. Bile detection is rarely performed, and herein, we aim to estimate the clinical significance of bile liquid biopsy by assessing bile exosomal concentrations and components. Approach &amp; Results: Exosomes in bile and sera from CCA, pancreatic cancer, and common bile duct stone were identified and quantified by transmission electronmicroscopy, nanoparticle tracking analysis, and nanoFCM. Exosomal components were assessed by liquid chromatography with tandem mass spectrometry and microRNA sequencing (miRNA-seq). Bile exosomal concentration in different diseases had no significant difference, but miR-182-5p and miR-183-5p were ectopically upregulated in CCA bile exosomes. High miR-182/183-5p in both CCA tissues and bile indicates a poor prognosis. Bile exosomal miR-182/183-5p is secreted by CCA cells and can be absorbed by biliary epithelium or CCA cells. With xenografts in humanized mice, we showed that bile exosomal miR-182/183-5p promotes CCA proliferation, invasion, and epithelial-mesenchymal transition (EMT) by targeting hydroxyprostaglandin dehydrogenase in CCA cells and mast cells (MCs), and increasing prostaglandin E2 generation, which stimulates PTGER1 and increases CCA stemness. In single-cell mRNA-seq, hydroxyprostaglandin dehydrogenase is predominantly expressed in MCs. miR-182/183-5p prompts MC to release VEGF-A release from MC by increasing VEGF-A expression, which facilitates angiogenesis. Conclusions: CCA cells secret exosomal miR-182/183-5p into bile, which targets hydroxyprostaglandin dehydrogenase in CCA cells and MCs and increases prostaglandin E2 and VEGF-A release. Prostaglandin E2 promotes stemness by activating PTGER1. Our results reveal a type of CCA self-driven progression dependent on bile exosomal miR-182/183-5p and MCs, which is a new interplay pattern of CCA and bile.
Prognosis and long‐term outcomes in type I cryoglobulinemia: A multicenter study of 168 patients
Authors: Amine Ghembaza, Gonçalo Boleto, Marin Bommelaer, Alexandre Karras, Vincent Javaugue, Frank Bridoux, Marie‐Alexandra Alyanakian, Valérie Molinier Frenkel, Pascale Ghillani‐Dalbin, Lucile Musset, Stéphane Barete, Damien Roosweil, Sylvain Choquet, Alexandre Le Joncour, Adrien Mirouse, Dan Lipsker, Stanislas Faguer, Matheus Vieira, Patrice Cacoub, Lucie Biard, David Saadoun
Journal: American Journal of Hematology (2023)

Type I cryoglobulinemia (CG) accounts for 10%-15% of all cryoglobulinemias and are exclusively seen in clonal proliferative hematologic conditions. In this multicenter nationwide cohort study, we analyzed the prognosis and long-term outcomes of 168 patients with type I CG (93 (55.4%) IgM and 75 [44.6%] IgG). Five- and 10-year event-free survivals (EFS) were 26.5% (95% CI 18.2%-38.4%) and 20.8% (95% CI 13.1%-33.1%), respectively. In multivariable analysis, factors associated with poorer EFS were renal involvement (HR: 2.42, 95% CI 1.41-4.17, p = .001) and IgG type I CG (HR: 1.96, 95% CI 1.13-3.33, p = 0.016), regardless of underlying hematological disorders. IgG type I CG patients had higher cumulative incidence of relapse (94.6% [95% CI 57.8%-99.4%] vs. 56.6% [95% CI 36.6%-72.4%], p = .0002) and death at 10 years (35.8% [19.8%-64.6%] vs. 71.3% [54.0%-94.2%], p = .01) as compared to IgM CG, respectively. Overall, complete response of type I CG at 6 months was 38.7%, with no significant difference between Igs isotypes. In conclusion, renal involvement and IgG CG were identified as independent poor prognostic factors of type I CG.
Targeting N-linked Glycosylation for the Therapy of Aggressive Lymphomas
Authors: Sebastian Scheich, Jiji Chen, Jiamin Liu, Frank Schnütgen, Julius C. Enssle, Michele Ceribelli, Craig J. Thomas, Jaewoo Choi, Vivian Morris, Tony Hsiao, Hang Nguyen, Boya Wang, Arnold Bolomsky, James D. Phelan, Sean Corcoran, Henning Urlaub, Ryan M. Young, Björn Häupl, George W. Wright, Da Wei Huang, Yanlong Ji, Xin Yu, Weihong Xu, Yandan Yang, Hong Zhao, Jagan Muppidi, Kuan-Ting Pan, Thomas Oellerich, Louis M. Staudt
Journal: Cancer Discovery (2023)

Abstract Diffuse large B-cell lymphoma (DLBCL) can be subdivided into the activated B-cell (ABC) and germinal center B cell–like (GCB) subtypes. Self-antigen engagement of B-cell receptors (BCR) in ABC tumors induces their clustering, thereby initiating chronic active signaling and activation of NF-κB and PI3 kinase. Constitutive BCR signaling is essential in some GCB tumors but primarily activates PI3 kinase. We devised genome-wide CRISPR–Cas9 screens to identify regulators of IRF4, a direct transcriptional target of NF-κB and an indicator of proximal BCR signaling in ABC DLBCL. Unexpectedly, inactivation of N-linked protein glycosylation by the oligosaccharyltransferase-B (OST-B) complex reduced IRF4 expression. OST-B inhibition of BCR glycosylation reduced BCR clustering and internalization while promoting its association with CD22, which attenuated PI3 kinase and NF-κB activation. By directly interfering with proximal BCR signaling, OST-B inactivation killed models of ABC and GCB DLBCL, supporting the development of selective OST-B inhibitors for the treatment of these aggressive cancers. Significance: DLBCL depends on constitutive BCR activation and signaling. There are currently no therapeutics that target the BCR directly and attenuate its pathologic signaling. Here, we unraveled a therapeutically exploitable, OST-B–dependent glycosylation pathway that drives BCR organization and proximal BCR signaling. This article is highlighted in the In This Issue feature, p. 1749
Immune checkpoint inhibitor-induced bullous pemphigoid is characterized by interleukin (IL)-4 and IL-13 expression and responds to dupilumab treatment
Authors: William D Shipman, Katelyn Singh, Jeffrey M Cohen, Jonathan Leventhal, William Damsky, Mary M Tomayko
Journal: British Journal of Dermatology (2023)

Immune checkpoint inhibitor-induced bullous pemphigoid (ICI-BP) is a clinically debilitating immune-related adverse event in need of novel therapeutic approaches, as conventional treatment can counteract intended tumour immunity. Here we demonstrate that interleukin (IL)-4 and IL-13 expression is elevated in ICI-BP similar to conventional autoimmune BP, and further demonstrate partial and complete disease clearance with dupilumab in four patients with ICI-BP. These data indicate that IL-4Rα inhibition may be a promising new therapy for ICI-BP.
BIN1, Myotubularin, and Dynamin-2 Coordinate T-Tubule Growth in Cardiomyocytes
Authors: Harmonie Perdreau-Dahl, David B. Lipsett, Michael Frisk, Fatemeh Kermani, Cathrine R. Carlson, Andreas Brech, Xin Shen, Anna Bergan-Dahl, Yufeng Hou, Tomi Tuomainen, Pasi Tavi, Peter P. Jones, Marianne Lunde, J. Andrew Wasserstrom, Jocelyn Laporte, Nina D. Ullrich, Geir Christensen, J. Preben Morth, William E. Louch
Journal: Circulation Research (2023)

Transverse tubules (t-tubules) form gradually in the developing heart, critically enabling maturation of cardiomyocyte Ca2+ homeostasis. The membrane bending and scaffolding protein BIN1 (bridging integrator 1) has been implicated in this process. However, it is unclear which of the various reported BIN1 isoforms are involved, and whether BIN1 function is regulated by its putative binding partners MTM1 (myotubularin), a phosphoinositide 3'-phosphatase, and DNM2 (dynamin-2), a GTPase believed to mediate membrane fission.We investigated the roles of BIN1, MTM1, and DNM2 in t-tubule formation in developing mouse cardiomyocytes, and in gene-modified HL-1 and human-induced pluripotent stem cell-derived cardiomyocytes. T-tubules and proteins of interest were imaged by confocal and Airyscan microscopy, and expression patterns were examined by RT-qPCR and Western blotting. Ca2+ release was recorded using Fluo-4.We observed that in the postnatal mouse heart, BIN1 localizes along Z-lines from early developmental stages, consistent with roles in initial budding and scaffolding of t-tubules. T-tubule proliferation and organization were linked to a progressive and parallel increase in 4 detected BIN1 isoforms. All isoforms were observed to induce tubulation in cardiomyocytes but produced t-tubules with differing geometries. BIN1-induced tubulations contained the L-type Ca2+ channel, were colocalized with caveolin-3 and the ryanodine receptor, and effectively triggered Ca2+ release. BIN1 upregulation during development was paralleled by increasing expression of MTM1. Despite no direct binding between MTM1 and murine cardiac BIN1 isoforms, which lack exon 11, high MTM1 levels were necessary for BIN1-induced tubulation, indicating a central role of phosphoinositide homeostasis. In contrast, the developing heart exhibited declining levels of DNM2. Indeed, we observed that high levels of DNM2 are inhibitory for t-tubule formation, although this protein colocalizes with BIN1 along Z-lines, and binds all 4 isoforms.These findings indicate that BIN1, MTM1, and DNM2 have balanced and collaborative roles in controlling t-tubule growth in cardiomyocytes.
Pharmacological and Nonpharmacological Supports in Shock
Authors: Quentin De Roux, Adrien Coëffic, Alexia Letord, Agathe Kudela, Nicolas Mongardon
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Pharmacological and Nonpharmacological Supports in Shock." American Journal of Respiratory and Critical Care Medicine, 208(2), pp. 196–198
Association of <i>Staphylococcus aureus</i> Colonization With Severity of Acute Radiation Dermatitis in Patients With Breast or Head and Neck Cancer
Authors: Yana Kost, Alexandra K. Rzepecki, Alana Deutsch, Mathew R. Birnbaum, Nitin Ohri, H. Dean Hosgood, Juan Lin, Johanna P. Daily, Kosaku Shinoda, Beth N. McLellan
Journal: JAMA Oncology (2023)

Importance Pathogenesis of acute radiation dermatitis (ARD) is not completely understood. Pro-inflammatory cutaneous bacteria may contribute to cutaneous inflammation after radiation therapy. Objective To evaluate whether nasal colonization with Staphylococcus aureus (SA) before radiation therapy is associated with ARD severity in patients with breast or head and neck cancer. Design, Setting, and Participants This prospective cohort study with observers blinded to colonization status was conducted from July 2017 to May 2018 at an urban academic cancer center. Patients aged 18 years or older with breast or head and neck cancer and plans for fractionated radiation therapy (≥15 fractions) with curative intent were enrolled via convenience sampling. Data were analyzed from September to October 2018. Exposures Staphylococcus aureus colonization status before radiation therapy (baseline). Main Outcomes and Measures The primary outcome was ARD grade using the Common Terminology Criteria for Adverse Event Reporting, version 4.03. Results Among 76 patients analyzed, mean (SD) age was 58.5 (12.6) years and 56 (73.7%) were female. All 76 patients developed ARD: 47 (61.8%) with grade 1, 22 (28.9%) with grade 2, and 7 (9.2%) with grade 3. The prevalence of baseline nasal SA colonization was higher among patients who developed grade 2 or higher ARD compared with those who developed grade 1 ARD (10 of 29 [34.5%] vs 6 of 47 [12.8%]; P = .02, by χ 2 test). Conclusions and Relevance In this cohort study, baseline nasal SA colonization was associated with development of grade 2 or higher ARD in patients with breast or head and neck cancer. The findings suggest that SA colonization may play a role in the pathogenesis of ARD.
Genome-Wide Identification of Gene Loss Events Suggests Loss Relics as a Potential Source of Functional lncRNAs in Humans
Authors: Zheng-Yang Wen, Yu-Jian Kang, Lan Ke, De-Chang Yang, Ge Gao
Journal: Molecular Biology and Evolution (2023)

Abstract Gene loss is a prevalent source of genetic variation in genome evolution. Calling loss events effectively and efficiently is a critical step for systematically characterizing their functional and phylogenetic profiles genome wide. Here, we developed a novel pipeline integrating orthologous inference and genome alignment. Interestingly, we identified 33 gene loss events that give rise to evolutionarily novel long noncoding RNAs (lncRNAs) that show distinct expression features and could be associated with various functions related to growth, development, immunity, and reproduction, suggesting loss relics as a potential source of functional lncRNAs in humans. Our data also demonstrated that the rates of protein gene loss are variable among different lineages with distinct functional biases.
Respiratory Effects of Traffic-Related Air Pollution: A Randomized, Crossover Analysis of Lung Function, Airway Metabolome, and Biomarkers of Airway Injury
Authors: Xinlei Zhu, Qingli Zhang, Xihao Du, Yixuan Jiang, Yue Niu, Yongjie Wei, Yang Zhang, Steven N. Chillrud, Donghai Liang, Huichu Li, Renjie Chen, Haidong Kan, Jing Cai
Journal: Environmental Health Perspectives (2023)

Background: Exposure to traffic-related air pollution (TRAP) has been associated with increased risks of respiratory diseases, but the biological mechanisms are not yet fully elucidated. Objectives: Our aim was to evaluate the respiratory responses and explore potential biological mechanisms of TRAP exposure in a randomized crossover trial. Methods: We conducted a randomized crossover trial in 56 healthy adults. Each participant was exposed to high- and low-TRAP exposure sessions by walking in a park and down a road with high traffic volume for 4 h in random order. Respiratory symptoms and lung function, including forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), the ratio of FEV1 to FVC, and maximal mid-expiratory flow (MMEF), were measured before and after each exposure session. Markers of 8-isoprostane, tumor necrosis factor-α (TNF-α), and ezrin in exhaled breath condensate (EBC), and surfactant proteins D (SP-D) in serum were also measured. We used linear mixed-effects models to estimate the associations, adjusted for age, sex, body mass index, meteorological condition, and batch (only for biomarkers). Liquid chromatography–mass spectrometry was used to profile the EBC metabolome. Untargeted metabolome-wide association study (MWAS) analysis and pathway enrichment analysis using mummichog were performed to identify critical metabolomic features and pathways associated with TRAP exposure. Results: Participants had two to three times higher exposure to traffic-related air pollutants except for fine particulate matter while walking along the road compared with in the park. Compared with the low-TRAP exposure at the park, high-TRAP exposure at the road was associated with a higher score of respiratory symptoms [2.615 (95% CI: 0.605, 4.626), p=1.2×10−2] and relatively lower lung function indicators [−0.075L (95% CI: −0.138, −0.012), p=2.1×10−2] for FEV1 and −0.190L/s (95% CI: −0.351, −0.029; p=2.4×10−2) for MMEF]. Exposure to TRAP was significantly associated with changes in some, but not all, biomarkers, particularly with a 0.494-ng/mL (95% CI: 0.297, 0.691; p=9.5×10−6) increase for serum SP-D and a 0.123-ng/mL (95% CI: −0.208, −0.037; p=7.2×10−3) decrease for EBC ezrin. Untargeted MWAS analysis revealed that elevated TRAP exposure was significantly associated with perturbations in 23 and 32 metabolic pathways under positive- and negative-ion modes, respectively. These pathways were most related to inflammatory response, oxidative stress, and energy use metabolism. Conclusions: This study suggests that TRAP exposure might lead to lung function impairment and respiratory symptoms. Possible underlying mechanisms include lung epithelial injury, inflammation, oxidative stress, and energy metabolism disorders. https://doi.org/10.1289/EHP11139
Addressing resistance to PD-1/PD-(L)1 pathway inhibition: considerations for combinatorial clinical trial designs
Authors: Tian Zhang, Patrick M Forde, Ryan J Sullivan, Elad Sharon, Elizabeth Barksdale, Wendy Selig, Scot Ebbinghaus, Gina Fusaro, Damla Gunenc, Dena Battle, Robyn Burns, Marc S Hurlbert, Mark Stewart, Michael B Atkins
Journal: Journal for ImmunoTherapy of Cancer (2023)

With multiple PD-(L)1 inhibitors approved across dozens of indications by the US Food and Drug Administration, the number of patients exposed to these agents in adjuvant, first-line metastatic, second-line metastatic, and refractory treatment settings is increasing rapidly. Although some patients will experience durable benefit, many have either no clinical response or see their disease progress following an initial response to therapy. There is a significant need to identify therapeutic approaches to overcome resistance and confer clinical benefits for these patients. PD-1 pathway blockade has the longest history of use in melanoma, non-small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Therefore, these settings also have the most extensive clinical experience with resistance. In 2021, six non-profit organizations representing patients with these diseases undertook a year-long effort, culminating in a 2-day workshop (including academic, industry, and regulatory participants) to understand the challenges associated with developing effective therapies for patients previously exposed to anti-PD-(L)1 agents and outline recommendations for designing clinical trials in this setting. This manuscript presents key discussion themes and positions reached through this effort, with a specific focus on the topics of eligibility criteria, comparators, and endpoints, as well as tumor-specific trial design options for combination therapies designed to treat patients with melanoma, NSCLC, or RCC after prior PD-(L)1 pathway blockade.
Hematopoietic progenitor kinase 1 inhibits the development and progression of pancreatic intraepithelial neoplasia
Authors: Hua Wang, Rohan Moniruzzaman, Lei Li, Baoan Ji, Yi Liu, Xiangsheng Zuo, Reza Abbasgholizadeh, Jun Zhao, Guangchao Liu, Ruiqi Wang, Hongli Tang, Ryan Sun, Xiaoping Su, Tse-Hua Tan, Anirban Maitra, Huamin Wang
Journal: Journal of Clinical Investigation (2023)

Ras plays an essential role in the development of acinar-to-ductal metaplasia (ADM) and pancreatic ductal adenocarcinoma (PDAC). However, mutant Kras is an inefficient driver for PDAC development. The mechanisms of the switching from low Ras activity to high Ras activity that are required for development and progression of pancreatic intraepithelial neoplasias (PanINs) are unclear. In this study, we found that hematopoietic progenitor kinase 1 (HPK1) was upregulated during pancreatic injury and ADM. HPK1 interacted with the SH3 domain and phosphorylated Ras GTPase-activating protein (RasGAP) and upregulated RasGAP activity. Using transgenic mouse models of HPK1 or M46, a kinase-dead mutant of HPK1, we showed that HPK1 inhibited Ras activity and its downstream signaling and regulated acinar cell plasticity. M46 promoted the development of ADM and PanINs. Expression of M46 in KrasG12D Bac mice promoted the infiltration of myeloid-derived suppressor cells and macrophages, inhibited the infiltration of T cells, and accelerated the progression of PanINs to invasive and metastatic PDAC, while HPK1 attenuated mutant Kras–driven PanIN progression. Our results showed that HPK1 plays an important role in ADM and the progression of PanINs by regulating Ras signaling. Loss of HPK1 kinase activity promotes an immunosuppressive tumor microenvironment and accelerates the progression of PanINs to PDAC.
Impact of clonal plasma cells in autografts on outcomes in high-risk multiple myeloma patients
Authors: Oren Pasvolsky, Denái R Milton, Mikael Rauf, Sassine Ghanem, Adeel Masood, Ali H Mohamedi, Mark R Tanner, Qaiser Bashir, Samer Srour, Neeraj Saini, Paul Lin, Jeremy Ramdial, Yago Nieto, Guilin Tang, Hans C Lee, Krina K Patel, Partow Kebriaei, Sheeba K Thomas, Donna M Weber, Robert Z Orlowski, Katy Rezvani, Richard Champlin, Elizabeth J Shpall, Pei Lin, Muzaffar H Qazilbash
Journal: Blood Cancer Journal (2023)

Abstract Most patients with multiple myeloma (MM) undergoing autologous hematopoietic stem cell transplantation (autoHCT) eventually relapse, perhaps due to the presence of clonal plasma cells (CPC) in the autograft. We conducted a retrospective analysis to evaluate the impact of CPC in the autograft on the outcomes of high-risk chromosomal abnormalities (HRMM) patients undergoing autoHCT between 2008 and 2018. Patients were divided into CPC+ or CPC− in the autograft by next-generation flow cytometry (NGF). There were 75 CPC + autografts (18%) and 341 CPC− (82%). The CPC + group was less likely to achieve MRD-negative complete remission post-transplant (11% vs. 42%; p &lt; 0.001). Median progression free survival (PFS) and overall survival (OS) were (12.8 vs. 32.1 months) and (36.4 vs. 81.2 months) in the CPC + and CPC− groups, respectively (both p &lt; 0.001). Also in the subset of patients with MRD-negative ≥VGPR prior to autoHCT, those with CPC + autografts had inferior PFS (HR 4.21, p = 0.006) and OS (HR 7.04, p = 0.002) compared to CPC-. In multivariable analysis, the degree of CPC positivity in the autograft was independently predictive of worse PFS (HR 1.50, p = 0.001) and OS (HR 1.37, p = 0.001). In conclusion, both the presence and degree of CPC in the autograft were highly predictive of inferior PFS and OS.